Design of bioactive compounds

Ariëns, E. J.; Simonis, A. M.

doi:10.1007/3-540-06873-2_13

Cited by 4 publications

(5 citation statements)

References 72 publications

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“…These are highly selective for the enzyme of mammals (rat) on the (Harms and Nauta, 1960 one hand and bacteria on the other (Fig. 18) (Hitchings, 1964;Ariens and Simonis, 1974). In conclusion, the accessory binding sites next to the active site on enzymes of different origin apparently can differ.…”

Section: Selectivity In Actionmentioning

confidence: 96%

“…In small agonist molecules, a differentiation is usually difficult to see between the groups in the molecule primarily involved in the receptor binding, the haptophore, and the groups primarily involved in the receptor activation, the actophore. Groups, especially those involved in pharmacon metabolism and pharmacon transport, are more easily recognizable (Ariens and Simonis, 1974;Ariens, 1971b). In larger bioactive molecules, especially polypeptides, programming for various aspects of the function may be localized in different amino acid sequences, as shown schematically in Fig.…”

Section: Structure and Actionmentioning

confidence: 99%

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The Pharmacon-Receptor-Effector Concept

Ariëns

Beld

Miranda

et al. 1979

General Principles and Procedures

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Section: Selectivity In Actionmentioning

confidence: 96%

Section: Structure and Actionmentioning

confidence: 99%

The Pharmacon-Receptor-Effector Concept

Ariëns

Beld

Miranda

et al. 1979

General Principles and Procedures

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“…However, low selectivity in the toxicity of traditional cationic surfactants may restrict their application, particularly with respect to therapeutic purposes. Side effects due to the persistence of biologically active compounds may be reduced through the design of analogs containing hydrolyzable bonds (2,6). This strategy was previously applied to cationic surfactants by Bodor et al (7) with a series of esters between quaternized a-aminoalcohols and fatty acids which were termed soft antimicrobial agents.…”

Section: Downloaded Frommentioning

confidence: 99%

Antimicrobial activity of betaine esters, quaternary ammonium amphiphiles which spontaneously hydrolyze into nontoxic components

Lindstedt

Allenmark

Thompson

et al. 1990

Antimicrob Agents Chemother

116

100

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A series of quaternary ammonium compounds that are esters of betaine and fatty alcohols with hydrocarbon chain lengths of 10 to 18 carbon atoms were tested with respect to antimicrobial activities and rates of hydrolysis. When the tetradecyl derivative was tested against some selected microorganisms, the killing effect was comparable to that of the stable quaternary ammonium compound cetyltrimethylammonium bromide. At higher pH values, both the antimicrobial effect and the rate of hydrolysis of the esters increased. However, whereas at pH 6 greater than 99.99% killing of Salmonella typhimurium was achieved with 5 ,ug/ml in 3 min, the rate of hydrolysis was less than 20% in 18 h. At pH 7, a similar killing effect was achieved in 2 min and 50% hydrolysis occurred in ca. 5 h. Thus, it is possible to exploit the rapid microbicidal effect of the compounds before they hydrolyze. The rate of hydrolysis was reduced by the presence of salt. The bactericidal effect of the betaine esters increased with the length of the hydrocarbon chain of the fatty alcohol moiety up to 18 carbon atoms. Since the hydrolysis products are normal human metabolites, the hydrolysis property may extend the use of these quaternary ammonium compounds as disinfectants and antiseptics for food and body surfaces.The membrane-disruptive and antimicrobial activities of cationic surfactants are well recognized. These agents are often active against a broad range of bacteria and other cells and can also inactive certain viruses (16,29). Because of their high affinity for biological membranes, these agents show a low selectivity and can be damaging to a variety of mammalian cells (17,23,24).Since the time needed to kill microorganisms with cationic surfactants is usually short, it could be expected that side effects in the host might be decreased by the use of substances that are subject to hydrolytic degradation. However, the lifetime of the compounds must be sufficiently long to allow proper inactivation of the undesired microorganisms. The products obtained in the degradation steps should also be significantly less toxic than the original compound and should ideally constitute normal metabolites of the host.To explore the possible use of degradable cationic surfactants, we studied a series of amphiphilic betaine esters (Fig. 1). Although the increased rate of base-catalyzed hydrolysis of lower esters of this structure has been investigated and is understood to be caused by an inductive effect from the positive charge (5, 26), this property does not seem to have been considered in connection with biological (10,27) or recent surface chemical (4, 25) studies of compounds of this type. In the present paper, we describe the synthesis of some esters between betaine (trimethylglycine) and long-chain fatty alcohols, their antimicrobial activities, and their rates of hydrolysis. MATERIALS AND METHODSCompounds investigated. The betaine esters were obtained as chlorides by chloroacetylation of the corresponding longchain alcohol, principally as described by Ho...

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“…0095-2338/82/1622-0207S01. 25/0 (1) The ability of a chemical compound to exert pharmacological action is determined by its capacity to bind complementarily and interact with the functional chemical structure in the living organism, i.e., the "receptor".…”

Section: Main Prerequisitesmentioning

confidence: 99%